In pharmacological research on hypertension, recent attention has focused on the study of the renin-angiotensin-aldosterone system, and, in particular, on the development of an effective anti-hypertensive agent which would, theoretically, achieve its result by inhibiting the action of angiotensin converting enzyme in converting angiotensin I to angiotensin II. The inhibition of the production of angiotensin II became important because of the discoveries that angiotensin II is the most potent pressor agent (vasoconstrictor) present in the mammalian body and, in addition, stimulates the adrenal cortex to release aldosterone, thereby causing excessive sodium retention and fluid retention, contributing further to the hypertensive state. Thus, inhibiting the conversion of angiotensin I to angiotensin II is believed to work directly on the primary biochemical mechanisms creating increased blood pressure. For a description of the mechanisms and of the mammalian renal-angiotensin-aldosterone system, see John H. Laragh, "The Renin System in High Blood Pressure, From Disbelief to Reality: Converting-Enzyme Blockade for Analysis and Treatment", Prog. in Cardio. Vasc. Disease, XXI, No. 3, 159-166 (November, 1978).
Recently, a series of proline derivatives has been found to act an inhibitors of angiotensin converting enzyme and as antihypertensive agents. Of these proline derivatives, D-3-mercapto-2-methylpropanoyl-L-proline has been reported to be the most effective, including being effective when administered orally. These proline and mercaptoproline derivatives and various pharmacological test results thereon are described in Cushman et al., "Design of New Anti-hypertensive Drugs: Potent and Specific Inhibitors of Angiotension Converting Enzyme", Prog. in Cardio. Diseases, Vol. XXI, No. 3 (Nov./Dec., 1978), and in U.S. Pat. Nos. 4,046,889 and 4,105,776, both to Ondetti and Cushman. Additionally, U.S. Pat. No. 4,225,495 to Ondetti discloses various hexahydro-1H,5H-pyrrolo[2,1-c][1,4]thiazepine-1,5-diones and tetrahydro-1H-pyrrolo[2,1-c][1,4]thiazine-1,4(3H)-diones as hypotensive agents. U.S. Pat. No. 4,225,495 also discloses 3-[L-prolylthio]-2-methylpropanoic acid and related compounds as intermediates for the production of said thiazepines and thiazines.